A culture model that enables research on the awakening of dormant malaria parasites

10 February 2014

The malaria parasite Plasmodium vivax, worldwide one of the most common causes of malaria in humans, can hide in the liver for years and, following an unknown trigger, cause disease. These dormant forms, called hypnozoites, are difficult to eliminate. Due to the inaccessibility of this stage of the parasite life cycle, very little is known about the biology of hypnozoites. As a result, drug targets for new treatment regimes that eliminate these stages are lacking. Therefore, the development of a culture system that enables research on the awakening of hypnozoites is very welcome.

Malaria parasites undergo a complicated life cycle. Following the bite of an infected mosquito, the parasites make their way to the liver, where they develop into thousands of new parasite forms. These forms can then invade red blood cells, causing disease. The parasite Plasmodium vivax has an additional developmental stage, as compared to many other malaria parasite species. This parasite can remain dormant in the liver, as so-called hypnozoites. Following reactivation of these stages, up to years after the primary infection, people can get clinical malaria and mosquitoes that bite the patient can subsequently transmit the parasite to other people. This is not only having health consequences for the patient, but is also problematic for the eradication of malaria, since the patient functions as ‘parasite reservoir’.

Hypnozoites are difficult to control because they are extremely insensitive to conventional antimalarial drugs. In-depth research on biological dormant liver stages is important to determine which pathways are active and to find targets for drug development. The monkey variant of P. vivax, P. cynomolgi, also forms hypnozoites, which we can detect in liver cell cultures. Clever adjustments of this culture system have now provided the opportunity to grow the infected liver cells long enough to detect reactivation (the awakening) of the dormant stages.

The reactivation can occur spontaneously, but treatment of the cultures with a particular agent induced awakening of the dormant parasites as well. This system will allow further analysis of these so far inaccessible stages of the malaria life cycle. In the long run, we hope to find a clinically applicable way to awaken these dormant stages, making them easier targets for currently available drugs.